Churg-Strauss syndrome (CSS) is a complex syndrome characterized by asthma, eosinophilic inflammation, and vasculitis involving multiple organs, including the lungs, heart, skin, gastrointestinal tract, and nervous system. CSS therapies (e.g. corticosteroids, cyclophosphamide, azathioprine) have multiple side effects, do not offer potential for long-term cure, and often fail to yield clinical benefit. To date, researchto study this 'orphan disease' has been minimal, its epidemiology, pathogenesis, and genetics remain largely unknown, and no significant therapeutic advances have been realized. As CSS is characterized by eosinophilic tissue infiltration, it appears that CSS is due to dysregulation of eosinophil function and/or production. Blood levels of interleukin-5 (IL-5), a cytokine regulating eosinophil bone marrow release, activation, and tissue survival, are increased in CSS patients. Anti-IL-5 antibody therapy represents a novel treatment that directly targets a primary pathophysiologic mechanism in CSS, decreasing eosinophil numbers in blood and bone marrow. This agent is safe and effective in hypereosinophilic syndromes and in eosinophilic asthma. We did an open label pilot trial of anti-IL5 (mepolizumab) in 10 CSS patients; anti-IL5 given for 4 months reduced CSS exacerbations, peripheral eosinophilia, and systemic corticosteroid dose. We thus hypothesize that anti-IL-5 will safely provide CSS patients a novel treatment that reduces CSS exacerbation rates, allows for corticosteroid tapering, and improves disease activity markers. To test this hypothesis, we propose a 1-year, double-blind, randomized placebo-controlled trial of anti-IL-5 in 54 CSS patients. This trial offers a unique opportunity for mechanistic studies that will result in identification of biomarkers of CSS disease activity and anti-IL5 responsiveness, and for molecular profiling studies that will provide insight into CSS genetics and pathogenesis. An NIAID Clinical Trial Planning Grant (R34) supported the planning and design of this clinical trial proposal (U01): a protocol, manuals of operations, case report forms, and IRB forms have been developed; plans for drug acquisition and distribution have been made; and we have organized a U01 study team with experts in CSS, eosinophilia, and vasculitis, and a data coordinating center that will execute this trial and mechanistic studies. With completion of this research, we will fulfill a significant unmet need, demonstrating efficacy and safety of a novel CSS therapy, gaining valuable insight into CSS pathogenesis, and a better understanding of aberrant eosinophil biology in CSS and other eosinophilic disorders.